Jason H. Mateika - US grants

[unreadable] DESCRIPTION (provided by applicant): A number of phenotypic traits may predispose humans to the development of obstructive sleep apnea (OSA). These traits may be altered over time in response to a variety of perturbations that accompany OSA, ultimately resulting in the exacerbation of this disorder. Our proposal will examine whether one phenotypic trait, the ventilatory sensitivity to carbon dioxide and oxygen, is increased in response to intermittent hypoxia (a hallmark of OSA), and whether this increase leads to exacerbation of OSA. Moreover, because oxidative stress following intermittent hypoxia has a role in enhancing respiratory drive in animals, we will examine whether this mechanism contributes to increases in ventilatory sensitivity and ultimately exacerbation of OSA. We will also determine whether treatment with antioxidants reverses this effect. To achieve our goals the following specific aims will be addressed: Specific Aim 1 is designed to measure the ventilatory response to carbon dioxide in the presence of sustained hypoxia and hyperoxia during wakefulness, using a modified rebreathing technique, before and after exposure to acute intermittent hypoxia (AIH) for 7 consecutive days (chronic intermittent hypoxia - CIH). Specific Aim 2 is designed to measure nocturnal respiratory drive and apnea severity before and after AIH, and to determine whether the impact of AIH on these measures is intensified after CIH. Measures of nocturnal respiratory drive will be obtained by examining changes in the ventilatory response to hypoxia and the rate of change of esophageal pressure during apnea. Specific Aims 3 & 4 will measure oxidative stress before and after AIH, and will determine whether antioxidant treatment mitigates increases in ventilatory sensitivity to carbon dioxide, nocturnal respiratory drive and ultimately apnea severity following exposure to AIH. The proposed aims are likely to yield critical insight into the impact that intermittent hypoxia has on ventilatory sensitivity and apnea severity. Moreover, our findings may provide the rationale for using antioxidants as a potential treatment for OSA. This treatment could be particularly useful in individuals who suffer from mild or moderate forms of OSA when used in conjunction with other potential innovative therapies. [unreadable] [unreadable] [unreadable]

Mild intermittent hypoxia (IH) initiates sustained increases in chest wall and upper airway muscle activity in humans. This sustained increase is a form of respiratory plasticity known as long-term facilitation (LTF). Repeated daily exposure to mild IH that leads to the initiation of LTF of upper airway muscle activity could lead to increased stability of the upper airway. In line with my laboratory?s mandate to develop innovative therapies to treat sleep apnea, this increased stability could ultimately reduce the continuous positive airway pressure (CPAP) required to treat obstructive sleep apnea (OSA) and improve compliance with this gold standard treatment. Improved compliance could ultimately serve to mitigate those co- morbidities linked to sleep apnea. Moreover, in addition to improving CPAP compliance numerous studies indicate that mild IH has many direct beneficial cardiovascular, neurocognitive and metabolic effects. Thus, mild IH could serve as a multipronged therapeutic approach to treat sleep apnea. In accordance with this postulation, Aim 1 of our proposal will determine if repeated daily exposure to mild IH serves as an adjunct therapy coupled with CPAP to mitigate associated co-morbidities via its direct effects on a variety of cardiovascular, metabolic and neurocognitive measures and indirectly by improving CPAP compliance. Modifications in autonomic (i.e. sympathetic nervous system activity) and cardiovascular (i.e. blood pressure) function will be the primary outcome measures coupled to secondary measures of metabolic and neurocognitive outcomes. Sleep is typically associated with a reduction in respiratory motoneuron excitability. This response is exacerbated and coupled to obstructive apneic events as a consequence of spinal cord injury induced morphological and neurological impairment of bulbospinal synaptic inputs to respiratory motoneurons, and adaptations in brainstem respiratory and upper airway motor function. These modifications are coupled to an incidence of sleep-disordered breathing (i.e. both central and obstructive sleep apnea) which is approximately 15 times higher in individuals with spinal cord injury than in the general population of the United States. Thus, exposure to this stimulus could improve CPAP compliance and enhanced outcome measures as outlined above. Additionally, repeated daily exposure to intermittent hypoxia promotes the recovery of respiratory and motor limb function in animals and humans. Thus, daily repeated exposure to IH could have significant therapeutic effects on respiratory and limb motor function in individuals with spinal cord injury accompanied by sleep apnea. Thus, Aim 2 of our proposal will serve to determine if IH can serve to mitigate co-morbidities linked to sleep apnea and promote the recovery of respiratory motor function during wakefulness and sleep, and motor limb function during wakefulness.